Imaging Dopamine-Mediated Neuro-Vascular Coupling

多巴胺介导的神经血管耦合成像

• 批准号: 6761969
• 负责人: Bruce G Jenkins
• 金额: $ 43.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761969
• 关键词: amphetamines; bioimaging /biomedical imaging; brain circulation; brain metabolism; cerebrovascular imaging /visualization; contrast media; corpus striatum; dopamine; dopamine agonists; dopamine antagonists; dopamine receptor; dopamine transporter; experimental brain lesion; frontal lobe /cortex; hemodynamics; laboratory rat; magnetic resonance imaging; microdialysis; model design /development; neuropharmacology; positron emission tomography; receptor binding; receptor coupling; receptor sensitivity; technology /technique development

DESCRIPTION (provided by applicant): The underlying goal of this project is to understand the molecular and synaptic processes that drive the hemodynamic response to a dopaminergic stimulus. This knowledge is crucial to proper interpretation of the changes observed in humans after pharmacologic challenges such as cocaine or amphetamine. First we will investigate the application of high magnetic susceptibility contrast agents to improve the MRI response to dopaminergic stimulation comparing pharmacological MRI (phMRI) measurements of blood oxygenation level dependent (BOLD) contrast or relative cerebral blood volume (rCBV). Then we will test the ability of selective dopamine D1 and D2 antagonists to block the phMRI signal changes induced via dopamine transporter blockers or amphetamine. Concurrently, we will test the hypothesis that hemodynamic changes are linearly proportional to dopamine concentrations by making microdialysis measurements of dopamine concentrations in striatum and frontal cortex. We will develop a quantitative model of CBV changes induced by dopaminergic stimulus combining the microdialysis information and receptor modeling. Then we will perform selective presynaptic dopamine fiber lesions using unilateral injections of 6-hydroxydopamine in the substantial nigra and selective unilateral lesioning of the postsynaptic striatal neurons using quinolinic acid injections. We will perform PET measurements of DAT, and D1 and D2 receptors to determine their correlations with the phMRI. Subsequently, we will examine the role of receptor supersensitivity using the lesion models above to determine the quantitative differences between the two striata after stimulation with apopmorphine or amphetamine, two compounds known to elicit opposite behavioral effects in these lesion models based upon dopamine receptor supersensitivity. These results will be correlated with quantitative PET measurements in the same animal of dopamine receptor binding properties. These studies should lead to a fundamental understanding of the synaptic and molecular underpinnings of behavioral - hemodynamic coupling which is crucial to use sophisticated neuroimaging tools like phMRI as well as fMR1. Ultimately, application of these tools will aid in developing a biological and physiological basis for understanding of human drug abuse.

描述(由申请人提供)： 这个项目的基本目标是了解驱动对多巴胺能刺激的血流动力学反应的分子和突触过程。这一知识对于正确解释在可卡因或安非他明等药物挑战后观察到的人类变化至关重要。首先，我们将研究应用高磁化率造影剂来改善MRI对多巴胺能刺激的反应，比较药理学MRI(PhMRI)测量的血氧水平依赖(BOLD)对比度或相对脑血容量(RCBV)。然后，我们将测试选择性多巴胺D1和D2拮抗剂阻断多巴胺转运体阻滞剂或苯丙胺诱导的phMRI信号变化的能力。同时，我们将通过对纹状体和额叶皮质的多巴胺浓度进行微透析测量，来检验血流动力学变化与多巴胺浓度成正比的假设。我们将结合微透析信息和受体模型建立多巴胺能刺激引起的CBV变化的定量模型。然后，我们将通过单侧黑质注射6-羟基多巴胺和使用喹啉酸注射选择性单侧损毁突触后纹状体神经元来进行选择性突触前多巴胺纤维损伤。我们将进行DAT、D1和D2受体的PET测量，以确定它们与phMRI的相关性。随后，我们将使用上面的损伤模型来研究受体超敏的作用，以确定在阿朴吗啡或苯丙胺刺激后两个纹状体之间的数量差异，这两种化合物已知在这些基于多巴胺受体超敏的损伤模型中引起相反的行为效应。这些结果将与同一动物的多巴胺受体结合特性的定量PET测量相关联。这些研究应该会导致对行为-血流动力学耦合的突触和分子基础的基本理解，这对于使用复杂的神经成像工具如phMRI和FMR1至关重要。最终，这些工具的应用将有助于发展理解人类药物滥用的生物学和生理学基础。